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Background: The reconstruction of individual patient data from published Kaplan-Meier survival curves is a new technique (often denoted as the IPDfromKM method) for studying efficacy in cases where multiple trials are available, and the endpoint is long-term mortality. In patients with tricuspid regurgitation, both valve repair and valve replacement have been proposed to improve prognosis; 6 controlled clinical trials (CTs) have been conducted to compare the two therapeutic options mentioned above. The objective of our analysis was to study these six trials through the application of the IPDfromKM method. Methods: In the present report, we applied the IPDfromKM method to carry out a pooled analysis of these 6 CTs to investigate the effectiveness of valve repair vs valve replacement and to assess the between-study heterogeneity from this clinical material. After reconstructing individual patient data from these 6 trials, patients treated with valve repair were pooled together and their Kaplan-Meier curve was generated. Likewise, patients treated with valve replacement were pooled together and their Kaplan-Meier curve was generated. Finally, these two curves were compared by standard survival statistics. The hazard ratio (HR) was determined; death from any cause was the endpoint. Results: These 6 CTs included a total of 552 patients; in each of these CTs, the patient group treated with valve repair was compared with another group treated with valve replacement. Our statistical results showed a significantly better survival for valve repair compared with valve replacement (HR, 0.6098; 95% confidence intervals (CI), 0.445 to 0.835; p = 0.002). Heterogeneity was found to be significant in the 6 patient arms undergoing replacement, but not in those undergoing valve repair. In valve replacement, the classification of patients in class III or IV of New York Heart Association (NYHA) was the main negative prognostic factor. Conclusions: Our analysis confirmed the methodological advantages of the IPDfromKM method in the indirect comparative analysis of multiple trials. These advantages include appropriate analysis of censored patients, original assessment of heterogeneity, and graphical presentation of the results, wherein individual patients retain an important role.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Ensayos Clínicos Controlados Aleatorios como Asunto , Reemplazo de la Válvula Aórtica Transcatéter , Humanos , Válvula Aórtica/cirugía , Reemplazo de la Válvula Aórtica Transcatéter/métodos , Estenosis de la Válvula Aórtica/cirugía , Masculino , Implantación de Prótesis de Válvulas Cardíacas/métodos , Femenino , Estimación de Kaplan-Meier , Tasa de Supervivencia/tendencias , Factores de Tiempo , Anciano , Factores de Riesgo , Resultado del TratamientoRESUMEN
When multiple treatments are available, network meta-analysis can synthesize evidence and rank relative effectiveness. We applied this approach to current treatments for previously untreated chronic lymphocytic leukaemia. Data search was conducted in PubMed and websites of regulatory agencies (year 2000 through present time). Our analysis included randomized controlled trials assessing treatments for previously untreated chronic lymphocytic leukaemia. The endpoint of the analysis was the rate of progression-free survival at 3 years. At least two reviewers abstracted study data and outcomes. Agents examined for their relative effectiveness included four monotherapies (chlorambucil, fludarabine, bendamustine, alemtuzumab) and four combination treatments (cyclophosphamide + fludarabine, cyclophosphamide + cladribine, cyclophosphamide + fludarabine + rituximab, cyclophosphamide + fludarabine + alemtuzumab). A Bayesian network meta-analysis was conducted to comparatively evaluate these treatments. Nine trials (3620 patients) were included in the analysis. Odds ratio (with 95 % credible intervals) was estimated for all direct and indirect comparisons. Combinations treatments were found to be significantly more effective than single-agent treatments. Ranking in effectiveness was as follows: (1) cyclophosphamide + fludarabine + rituximab, (2) alemtuzumab, (3) cyclophosphamide + fludarabine + alemtuzumab, (4) cyclophosphamide + fludarabine and (at same ranking) cyclophosphamide + cladribine, (6) fludarabine, (7) bendamustine and (8) chlorambucil. Bendamustine fared worse in our analysis than in its pivotal trial. Overall, the estimated rankings appeared to be robust according to probabilistic analysis. Numerous indirect comparisons were assessed in the absence of RCTs. In conclusion, we generated an updated synthesis of the effectiveness of these treatments and we ranked them according to a Bayesian probabilistic model. In our probabilistic analysis, cyclophosphamide + fludarabine + rituximab ranked first in the base case while the worst-case scenario of this analysis placed this treatment at a remarkable second place.
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Antineoplásicos/administración & dosificación , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Estadística como Asunto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Estadística como Asunto/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: In studying the comparative effectiveness of novel oral anticoagulants (NOACs) in orthopedic surgery and in non-valvular atrial fibrillation, previous meta-analyses have found no proof of difference in head-to-head indirect comparisons between individual agents. However, the question of their therapeutic equivalence remains unanswered. OBJECTIVES: The objective of this analysis was to test the equivalence of three NOACs (dabigatran, rivaroxaban, apixaban) in orthopedic surgery and four NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) in non-valvular atrial fibrillation. METHODS: Standard pairwise meta-analysis and network meta-analysis for indirect comparisons were combined with equivalence testing. The endpoint was venous thromboembolism in orthopedic surgery and a composite of stroke or systemic embolism in atrial fibrillation. Comparisons were expressed as risk difference (RD). Margins for equivalence testing were derived from the original trials. RESULTS: Our results indicate that rivaroxaban and apixaban (but not dabigatran) are equivalent for thromboprophylaxis in orthopedic surgery. In atrial fibrillation, all the four NOACs we tested were found to meet the criterion of therapeutic equivalence. Some concern, however, is raised by some findings focused on adverse events of these agents, in which the equivalence was not proven in all analyses. CONCLUSIONS: Regardless of clinical implications, our results can be the basis to develop local acquisition tenderings on NOACS. In Italy, a new law has been issued according to which equivalence analyses have become a mandatory prerequisite for local tenderings.
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Anticoagulantes/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Coagulación Sanguínea/efectos de los fármacos , Procedimientos Ortopédicos/efectos adversos , Accidente Cerebrovascular/prevención & control , Tromboembolia Venosa/prevención & control , Administración Oral , Anticoagulantes/efectos adversos , Fibrilación Atrial/sangre , Fibrilación Atrial/complicaciones , Bencimidazoles/administración & dosificación , Dabigatrán , Humanos , Morfolinas/administración & dosificación , Seguridad del Paciente , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Piridonas/administración & dosificación , Medición de Riesgo , Rivaroxabán , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/etiología , Equivalencia Terapéutica , Tiazoles/administración & dosificación , Tiofenos/administración & dosificación , Resultado del Tratamiento , Tromboembolia Venosa/sangre , Tromboembolia Venosa/etiología , beta-Alanina/administración & dosificación , beta-Alanina/análogos & derivadosRESUMEN
BACKGROUND: In the present study, we undertook an equivalence analysis on the effectiveness of the main anti-reabsorptive agents indicated for women with osteoporosis. METHODS: Our methodology was a combination of meta-analysis (both pair-wise meta-analysis and network meta-analysis) and equivalence testing. The end-point was the incidence on new vertebral fractures. The anti-reabsorptive agents examined included alendronate, zoledronate, ibandronate, risedronate, and denosumab. RESULTS: Our analysis involved nine randomized trials. Ten head-to-head indirect comparisons were examined through network meta-analysis and the respective values of RR were estimated. The 95 % confidence intervals for RR remained within the interval of a relative ±40 % variation for all comparisons that involved alendronate, risedronate, ibandronate, and denosumab. In contrast, the comparisons involving zoledronate satisfied a post hoc margin up to ±67 %. CONCLUSION: Our results confirm that most of these anti-reabsorptive drugs (namely, alendronate, risedronate, ibandronate, and denosumab) are equivalent according to reasonable equivalence margins.
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Conservadores de la Densidad Ósea/uso terapéutico , Medicina Basada en la Evidencia , Osteoporosis Posmenopáusica/tratamiento farmacológico , Fracturas Osteoporóticas/prevención & control , Fracturas de la Columna Vertebral/prevención & control , Alendronato/farmacocinética , Alendronato/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Conservadores de la Densidad Ósea/farmacocinética , Denosumab , Difosfonatos/farmacocinética , Difosfonatos/uso terapéutico , Ácido Etidrónico/análogos & derivados , Ácido Etidrónico/farmacocinética , Ácido Etidrónico/uso terapéutico , Femenino , Humanos , Ácido Ibandrónico , Incidencia , Osteoporosis Posmenopáusica/metabolismo , Osteoporosis Posmenopáusica/fisiopatología , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/etiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Ácido Risedrónico , Fracturas de la Columna Vertebral/epidemiología , Fracturas de la Columna Vertebral/etiología , Equivalencia TerapéuticaRESUMEN
BACKGROUND: Although intravenous proton pump inhibitors (PPIs) are considered at least as effective as H2-receptors antagonists for stress ulcer prophylaxis (SUP) in critically ill patients, there is no data on whether there is also the proof of no difference among these agents. METHODS: The clinical material was the same as that reported in previous meta-analyses and included all trials comparing intravenous PPIs vs. H2-receptor antagonists for SUP in critically ill patients. Our methodology was a combination of meta-analysis and equivalence testing based on confidence intervals (CIs). The end-point was the rate of overt bleeding. All PPIs evaluated in the included trials were separately studied. The equivalence margins were derived from power calculation data of the original trials. RESULTS: Our analysis involved 8 randomized trials for 851 patients. Two comparisons were made (pantoprazole vs. H2-receptor antagonists and omeprazole vs. H2-receptor antagonists). The following RDs were estimated: pantoprazole, RD = -1.2%, 95% CI: -3.5% to +1.2%; omeprazole, RD = -3.0%, 95% CI: -7.2% to +1.3%. The 95% CIs confidence intervals for RDs remained within the ± 6% margin. These results indicate that intravenous pantoprazole and intravenous omeprazole are equivalent, Conclusion: These two PPIs, when administered by intravenous route, are equivalent according to reasonable equivalence margins. This conclusion can be the basis to develop local acquisition tenders on these drugs. One advantage of this approach is that the feasibility of administrative decisions can directly be tested on clinical grounds and on the basis of standard evidence-based methods.
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Úlcera Péptica/prevención & control , Inhibidores de la Bomba de Protones/uso terapéutico , Estrés Psicológico/complicaciones , Administración Intravenosa , Enfermedad Crítica , Medicina Basada en la Evidencia , Antagonistas de los Receptores H2 de la Histamina/uso terapéutico , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Although MitraClip has been studied in numerous trials, its evidence in the long term is based on a few original studies. We used an original technique of evidence synthesis to review long-term comparative trials evaluating MitraClip. We searched the PubMed database to select long-term comparative trials of MitraClip. The endpoint was all-cause mortality (minimum follow-up, one year). Included trials were analyzed using the IPDfromKM (reconstruct Individual Patient Data from published Kaplan-Meier survival curves) method to reconstruct individual patient data from Kaplan-Meier curves. Standard survival statistics were used to interpret these long-term efficacy data. The survival benefit per patient was estimated from the restricted mean survival time (RMST). Six comparative studies of MitraClip were included; 973 patients were treated with MitraClip (six arms), 717 with medical therapy (five arms), and 80 with surgical repair or replacement (one arm). In our main analysis, the outcomes observed in patients treated with MitraClip were significantly better than those of medical therapy (hazard ratio for all-cause mortality, 0.5276; 95% confidence interval, 0.4412 to 0.6309; p < 0.001); the number of patients treated with surgery was too small to make reliable comparisons. Median survival was 30.4 months for medical therapy versus not reached for the other two groups. RMST was 43.931 and 33.756 months for MitraClip and controls, respectively, yielding a gain per patient of 10.17 months (95% confidence interval, 7.47 to 12.88). In our simplified cost-effectiveness evaluation, a gain of approximately 10 months per patient compared favorably with the device cost. Our analysis provided an original interpretation of the long-term evidence available on MitraClip.
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Background: CardioMEMS is a device suitable for telemedicine that is currently being evaluated by the Regional Health Technology Assessment (HTA) Committee of Tuscany. Two detailed HTA reports are available in the specialized literature, the results of which need to be transferred to our regional setting. These decisions in Tuscany are made by the so-called Centro Operativo HTA. Aim: To validate, with local cost-effectiveness data, the decision on CardioMEMS that will be made in the Tuscany region. Methods: Two detailed international HTA reports were rearranged and adapted to our regional setting to generate a simplified analysis that could form the basis of our decision. Two willingness-to-pay (WTP) thresholds of 20,000/quality-adjusted life year (QALY) and 50,000/QALY were considered. Results: Based on epidemiological and regulatory information, the target population in Tuscany for this device is 166 cases. The value-based price of CardioMEMS is estimated to be 4,332 and 16,662 at WTP thresholds of 20,000/QALY and 50,000/QALY, respectively. Its current price in Italy is 12,000. Conclusion: In our region, the introduction of CardioMEMS is likely to be gradual, around 50 patients/year (or 0.60 million/year at current price). This example highlights the need to adapt the information published in the international literature to the local context in which the approval decision is made. In this context, simplified analyses are easier to apply than complex Markov models.
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BACKGROUND: Canonical α/ß T-cell receptors (TCRs) bind to human leukocyte antigen (HLA) displaying antigenic peptides to elicit T cell-mediated cytotoxicity. TCR-engineered T-cell immunotherapies targeting cancer-specific peptide-HLA complexes (pHLA) are generating exciting clinical responses, but owing to HLA restriction they are only able to target a subset of antigen-positive patients. More recently, evidence has been published indicating that naturally occurring α/ß TCRs can target cell surface proteins other than pHLA, which would address the challenges of HLA restriction. In this proof-of-concept study, we sought to identify and engineer so-called HLA-independent TCRs (HiTs) against the tumor-associated antigen mesothelin. METHODS: Using phage display, we identified a HiT that bound well to mesothelin, which when expressed in primary T cells, caused activation and cytotoxicity. We subsequently engineered this HiT to modulate the T-cell response to varying levels of mesothelin on the cell surface. RESULTS: The isolated HiT shows cytotoxic activity and demonstrates killing of both mesothelin-expressing cell lines and patient-derived xenograft models. Additionally, we demonstrated that HiT-transduced T cells do not require CD4 or CD8 co-receptors and, unlike a TCR fusion construct, are not inhibited by soluble mesothelin. Finally, we showed that HiT-transduced T cells are highly efficacious in vivo, completely eradicating xenografted human solid tumors. CONCLUSION: HiTs can be isolated from fully human TCR-displaying phage libraries against cell surface-expressed antigens. HiTs are able to fully activate primary T cells both in vivo and in vitro. HiTs may enable the efficacy seen with pHLA-targeting TCRs in solid tumors to be translated to cell surface antigens.
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Mesotelina , Neoplasias , Humanos , Linfocitos T CD8-positivos , Receptores de Antígenos de Linfocitos T , Antígenos de Neoplasias/metabolismo , Neoplasias/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Péptidos/metabolismo , Antígenos de Histocompatibilidad/metabolismoRESUMEN
In patients with acute lymphoblastic leukemia in first complete remission, several studies have compared allogeneic transplant with autologous transplant or chemotherapy. This material can be the basis for analyzing the temporal trend of outcomes. Our study was designed as a meta-regression focused on temporal trends and based on the endpoint of 5-year leukemia-free survival (5yLFS). Studies in which 5yLFS was determined in a patient group subjected to allogeneic transplant and in a control group (treated with autologous transplant and/or chemotherapy) were eligible for our meta-analysis. A standard literature search was carried out to identify pertinent studies. The results of included studies were submitted to an observational meta-analysis and to a meta-regression focused on two covariates (calendar year in which the study was conducted; percentage of high-risk patients). The endpoint of 5yLFS was separately assessed between allogeneic transplant and autologous transplant or chemotherapy. Our analysis included 14 studies that covered a period (1983 to 1999) in which patients were conditioned only with myeloablative conditioning and not with non-myeloablative ones. In the risk ratio (RR) analysis, the pooled outcome showed a significantly better profile for allogeneic transplantation (RR = 1.42; 95 % confidence interval (CI), 1.22 to 1.65). Separate analysis of the two treatment options found a pooled 5yLFS of 45 % (95 % CI, 38 to 51 %) for allogeneic transplant vs 30 % (95 % CI, 23 to 37 %) for the controls. In meta-regression, the temporal trend analysis revealed that, in patients subjected to allogeneic transplant, the values of 5yLFS showed no significant change over the 16-year interval (p = 0.720); the same stability over time was found in the control group (p = 0.489). On the other hand, the percentage of high-risk patients influenced outcomes in both patient groups at levels of statistical significance (p = 0.014 and p = 0.045 in the allotransplant group and in the controls, respectively). Our results can represent a reference point for future analyses focused on patients treated in more recent years.
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Antineoplásicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirugía , Ensayos Clínicos como Asunto/métodos , Estudios de Seguimiento , Humanos , Inducción de Remisión/métodos , Factores de Tiempo , Trasplante Autólogo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
In medical devices, recent studies have proposed original approaches for standardizing competitive tenders with the aim of promoting reproducibility, avoiding discretional decisions, and applying value-based principles. In the framework of tenders' standardization, the net monetary benefit (NMB) method has attracted much interest, but its mathematical complexity has prevented a wide application. In the present work, we developed a procurement model that simplifies clinical information management for high-technology devices purchased for our public hospitals. Our objective was to promote the application of NMB in competitive tenders, particularly at the final stage of the procurement process, where the tender scores are determined. Software to facilitate this task in everyday practice has been developed. This software is made available through the present technical report. We surveyed the most relevant literature about NMB to select the main models commonly used in the studies published thus far. Standard equations of cost-effectiveness were identified. A simplified computation model based on three clinical endpoints was developed to estimate the NMB with less mathematical complexity. This model is proposed as an alternative to the standard approach based on a full economic analysis. The model developed herein has been implemented in a web-based software freely available on the Internet. This software is accompanied by a detailed description of the equations by which the NMB is estimated. A detailed application example is reported; a real tender carried out in 2021 has been re-examined for this purpose. In this re-analysis, the new software has been used to calculate the NMB of three devices. To our knowledge, this is the first experience in which an institution of the Italian healthcare system has evaluated the NMB as a tool for determining tender scores. The model is designed to offer performance similar to a full economic analysis. Our preliminary results are encouraging and suggest a wider application of this method. This approach has important implications regarding cost-effectiveness and cost containment because a value-based procurement is known to maximize effectiveness without determining an increase in costs.
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Time-to-event endpoints are most widely used in oncology and, to a lesser extent, in cardiology. Typical statistical parameters employed in this context include overall survival, progression-free survival, and recurrence-free survival. The graphical presentation of the results is based on the Kaplan-Meier plot. When Kaplan-Meier curves are included in a meta-analysis, the typical methodological approach is a simplified one because the results of each trial (as well as those of the meta-analysis itself) are expressed through a 2x2 contingency; the methodological simplification is that the follow-up is left out from the analysis and, consequently, the Kaplan-Meier curves are omitted as well. The IPDfromKM method, developed in 2021, is an artificial intelligence algorithm designed to be used in these situations. According to this method, to keep the Kaplan-Meier curves in the meta-analysis, each curve is converted into a database of individual patients (which are denoted as "reconstructed" individual patients). In this way, for the purposes of the meta-analysis, the statistical methods are based on individual patients (like those of clinical trials) so that the Kaplan-Meier curves must not be excluded, and the effect of the follow-up can, therefore, be investigated. This technical report describes the IPDfromKM method in all of its operational details. To present the method, a meta-analysis investigating the effects of catheter ablation to prevent ventricular tachyarrhythmia (VT) has been taken as an example. The original meta-analysis, which included nine controlled trials, was published in February 2023 and adopted the simplified approach based on 2x2 contingency tables. We have reanalyzed these trials by using the IPDfromKM method. Overall, both the standard binary meta-analysis and the IPDfromKM method showed that ablation significantly reduces VT recurrence (hazard ratio, 0.820 for binary meta-analysis vs 0.728 for the IPDfromKM method). By contrast, while no heterogeneity was found by the binary method, the IPDfromKM found significant heterogeneity, which was confirmed by visual inspection of the Kaplan-Meier curves. This suggests that the results of the IPDfromKM method are more accurate because they include the effect of the follow-up on patients' outcomes. In conclusion, our reanalysis confirms the significant benefit determined by ablation, but a more pronounced degree of between-trial heterogeneity has been found. Finally, it should be stressed that, outside the field of meta-analysis, the IPDfromKM method is also applicable to carry out an indirect comparison between treatments that have never been compared in real clinical trials. In this case, reconstructed patients are analyzed by conducting a simulated comparative trial.
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OBJECTIVES: Oral drugs for relapsing-remitting multiple sclerosis (RRMS) have been recently investigated and, one of these, fingolimod, is already available in several countries. In this framework, an analysis of the data in terms of the comparative effectiveness for all treatments thus far approved for RRMS can be useful to reappraise their place in therapy. METHODS: After a MEDLINE search, we selected all randomised trials studying the effectiveness of drugs for RRMS and included in our analysis those randomised trials in which interferon, glatiramer, natalizumab or fingolimod were studied. The end-point was the relapse-free rate at 12 months, which was compared between the various treatments. Direct comparisons, based on actual randomised trials, were handled by calculating the trial-specific hazard ratio (HR) or the meta-analytic value of HR (when at least 2 trials were available). Indirect comparisons for which data from actual trials were missing were instead managed through a network meta-analysis. RESULTS: Ten randomised trials met the criteria set for our analysis. All active treatments were found to be significantly more effective than placebo (direct comparisons) in terms of freedom from relapse at the 12-month follow-up assessments; the values of HR ranged from 1.28 for glatiramer to 1.53 for interferon beta. The comparisons between active agents revealed that fingolimod was superior to interferon (HR = 1.18; direct comparison) and glatiramer (HR = 1.23; indirect comparison), while the other four head-to-head comparisons of treatments revealed no significant difference. CONCLUSIONS: On the basis of the effectiveness data presently available, fingolimod seems to offer the advantage of oral administration together with the most favorable profile in terms of relapse-free rate at the 1-year follow-up assessment.
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Inmunosupresores/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Anticuerpos Monoclonales Humanizados/uso terapéutico , Clorhidrato de Fingolimod , Acetato de Glatiramer , Humanos , Interferón beta/uso terapéutico , Natalizumab , Péptidos/uso terapéutico , Esfingosina/uso terapéuticoRESUMEN
A "simplified" figure was proposed in 2011 to summarize the results of controlled trials that evaluate different treatments aimed at the same disease condition. The original criteria for classifying individual binary comparisons included superiority, inferiority and no significance difference; hence, they did not differentiate between no proof of difference vs proof of no difference. We updated the criteria employed in the original "simplified" figure in order to include this differentiation. A revised version of the simplified figure is proposed and described herein. An example of application is also presented. The example is focused on first-line treatments for paroxysmal atrial fibrillation. Three treatments (medical therapy, cryoballoon ablation, radiofrequency ablation) are compared with one another through direct and indirect comparisons.
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HCV vaccine development is stymied by the high genetic diversity of the virus and the variability of the envelope glycoproteins. One strategy to overcome this is to identify conserved, functionally important regions-such as the epitopes of broadly neutralizing antibodies (bNAbs)-and use these as a basis for structure-based vaccine design. Here, we report an anti-idiotype approach that has generated an antibody that mimics a highly conserved neutralizing epitope on HCV E2. Crucially, a mutagenesis screen was used to identify the antibody, designated B2.1 A, whose binding characteristics to the bNAb AP33 closely resemble those of the original antigen. Protein crystallography confirmed that B2.1 A is a structural mimic of the AP33 epitope. When used as an immunogen B2.1 A induced antibodies that recognized the same epitope and E2 residues as AP33 and most importantly protected against HCV challenge in a mouse model.